Development of receptors for N-methylated lysine- and arginine-derivatives

在这个项目中，我们建议开发的超分子受体的荧光为基础的检测甲基化赖氨酸和精氨酸衍生物。赖氨酸和精氨酸侧链的翻译后修饰（PTM）对于基因的调控和表达具有重要功能，因此用于其检测和定量的分析工具将具有高价值。由于目前还没有针对这些PTMs的人工合成受体，因此我们提出了一个模块化的概念来开发合适的受体，并将其用于检测部分甲基化的PTMs（如Kme、Kme 2、Rme、sRme 2）。首先，将基于BINOL-磷酸合成合适的一级结合基序，允许与甲基化氨基和胍基的选择性相互作用。BINOL-磷酸酯允许基于几种非共价相互作用与这些氨基酸侧链相互作用，最重要的是氢键和阳离子-π-相互作用。这些初级结合基序然后将被整合到多齿受体中，所述多齿受体具有额外的次级结合基序。这意味着提供足够的结合亲和力，特别是在水性环境中。所得受体随后将用于鉴定和定量甲基化赖氨酸和精氨酸衍生物。我们将使用逐步的方法，从分离的氨基酸开始，然后是短肽，最后是整个组蛋白。如果成功的话，新开发的受体将首次允许简单的，基于荧光的部分甲基化赖氨酸和赖氨酸的鉴定，从而代表一个有价值的（生物）分析工具。

Within this project, we suggest the development of supramolecular receptors for a fluorescence-based detection of methylated lysine- and arginine-derivatives. The posttranslational modification (PTM) of lysine and arginine sidechains has an important function for the regulation and expression of genes, so that analytical tools for their detection and quantification would be of high value. The proposed receptors are especially designed for the detection of partially methylated Derivates (such as Kme, Kme2, Rme, sRme2), because no synthetic receptors have yet been developed for these PTMs.For the development of suitable receptors, we suggest a modular concept. First, suitable primary binding motifs will be synthesized based on BINOL-phosphates, allowing a selective interaction with the methylated amino- and guanidino-groups. BINOL-phosphates allow the interaction with these amino-acid sidechains based on several noncovalent interactions, most importantly hydrogen-bonding and cation-pi-interactions. These primary binding motifs will then be integrated into multidentate receptors, which possess additional secondary binding motifs. This is meant to give sufficient binding affinities, especially in an aqueous environment. The resulting receptors will subsequently be applied for the identification and quantification of methylated lysine- and arginine-derivatives. We will use a stepwise approach, starting with isolated amino acids, followed by short peptides and finally entire histone proteins.If successful, the newly developed receptors would allow a simple, fluorescence-based identification of partially methylated lysines and arginines for the first time, thus representing a valuable (bio)analytical tool.